Autism and dyslexia susceptibility genes identified


In a collaborative study led by scientists based at the Wellcome Trust Centre for Human Genetics (WTCHG), Bologna University (Italy) and Utrecht University Medical Center (the Netherlands), rare genetic variation in two genes, CNTNAP5 and DOCK4, has been linked to autism and dyslexia susceptibility.

Dr Pagnamenta from the WTCHG and colleagues probed the entire genome of an individual with autism using over 1 million short (50 letter) pieces of DNA.  By looking for decreases in average signal coming from these probes, they found two large deletions: a section of 227,000 missing letters of DNA was detected on chromosome 2, whilst a second deletion of 594,000 letters was identified on chromosome 7.  These two changes, inherited from the boy's father and mother respectively, were also present in the boy's affected brother.  In addition, the chromosome 7 deletion was present in a number of relatives with reading difficulties.

Mar 10 autism and dyslexiaThe researchers also looked at the effect of the chromosome 7 deletion on the relevant "transcripts" - the molecular messengers that transfer information between genes and the cell's protein synthesis machinery.  They show that the deletion leads to a fused transcript made up of the first half of DOCK4 and the second half of the neighbouring gene (see figure).  Further studies should determine whether fusion transcripts are a common feature of genetic deletions.  Although in this case, the fusion transcript is unstable, these type of transcripts have the potential to result in proteins that have never been seen before, and which can disrupt normal cellular function.

As neither of these deletions were seen in 2,091 individuals from the general population, the researchers then proposed that they may act as risk factors for autism and dyslexia.  In their study, published online in Biological Psychiatry today (29th March 2010), the CNTNAP5 gene was sequenced in individuals with autism and additional rare variants were detected in 4/523 cases.  Working in collaboration with scientists from many other European research centres, they also found one other DOCK4 deletion amongst 606 individuals with dyslexia that had been inherited from a father reported to have had dyslexia in childhood.

Interestingly, CNTNAP5 is closely related to other genes that can influence susceptibility to autism, such as CNTNAP2, which was first identified in 2008.  DOCK4 is thought to be involved in the growth and development of nerve cells in the brain.  Together, these results may open up new lines of research to help understand mechanisms behind neurological disorders and brain development.

This study also highlights how different rare mutations can combine within a single family to give rise to a range of neurological phenotypes. Further investigations will be required to show if having multiple rare deletions is a common feature in neuropsychiatric disease genetics.  Although these results will not directly lead to a cure, this improved understanding of genetic factors that play a role in autism may improve early diagnosis and the benefits that might bring.

For more information on Dr Pagnamenta's research, click here.